title: Energetic pathway sampling in a protein interaction domain.
abstract: The affinity and specificity of protein-ligand interactions are influenced by energetic crosstalk within the protein domain. However, the molecular details of such intradomain allostery are still unclear. Here, we have experimentally detected and computationally predicted interaction pathways in the postsynaptic density 95/discs large/zonula occludens 1 (PDZ)-peptide ligand model system using wild-type and circularly permuted PDZ proteins. The circular permutant introduced small perturbations in the tertiary structure and a concomitant rewiring of allosteric pathways, allowing us to describe how subtle changes may reshape energetic signaling. The results were analyzed in the context of other members of the PDZ family, which were found to contain distinct interaction pathways for different peptide ligands. The data reveal a fascinating scenario whereby several energetic pathways are sampled within one single domain and distinct pathways are activated by specific protein ligands.
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.
authors.forename: Greta
authors.initials: G
authors.lastname: Hultqvist
authors.forename: S Raza
authors.initials: SR
authors.lastname: Haq
authors.forename: Avinash S
authors.initials: AS
authors.lastname: Punekar
authors.forename: Celestine N
authors.initials: CN
authors.lastname: Chi
authors.forename: Åke
authors.initials: Å
authors.lastname: Engström
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.forename: Maria
authors.initials: M
authors.lastname: Selmer
authors.forename: Stefano
authors.initials: S
authors.lastname: Gianni
authors.forename: Per
authors.initials: P
authors.lastname: Jemth
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics; D000495:Allosteric Site; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000074288:Discs Large Homolog 1 Protein; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D054731:PDZ Domains; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C513314:DLG1 protein, human; D000074288:Discs Large Homolog 1 Protein; D008565:Membrane Proteins